The long-term objective of this research is understanding how long-term nicotine use and subsequent nicotine withdrawal alter the normal functioning of synapses in the hippocampus. Cigarette smoking and acute and chronic administration of nicotine can enhance cognitive function, a property that has been linked with the continued use of cigarettes. Our studies have demonstrated that acute and chronic nicotine exposure facilitate the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP; considered to be a cellular substrate for learning and memory) in the hippocampus. Following nicotine withdrawal, however, the threshold for LTP induction fluctuates and nicotine is no longer effective in facilitating the induction of LTP. These nicotine effects may represent the cellular basis of nicotine-mediated cognitive enhancement and unpleasant withdrawal symptoms, contributing to cigarette-seeking behavior. Nicotine enhances NMDAR responses in pyramidal cells via three different pathways, two involving disinhibition of pyramidal cells and the other involving activation of muscarinic acetylcholine receptors (AChRs). Our working hypothesis is that long-term nicotine exposure and withdrawal differentially alter these pathways, affecting NMDAR responses and thereby LTP induction. The proposed experiments will test this hypothesis by identifying altered pathways in hippocampi from chronic-nicotine-treated and withdrawn rats with combinations of electrophysiological, histochemical, and molecular biological approaches. The specific aims are to determine: (1) which pathways of nicotine action, leading to the enhancement of NMDAR responses, are altered, (2) if the normal functioning of a7 and non-a7 nicotinic AChRs on GABAergic interneurons are affected, (3) if feedforward GABAergic inhibition is altered, and (4) if muscarinic AChR-mediated signaling is affected. Results from these studies are expected to provide significant insights into mechanisms that underlie nicotine dependence, which may aid in the development of novel therapeutic strategies.